OVERVIEW: What every practitioner needs to know

Are you sure your patient has HIV infection? What should you expect to find?

Chronic HIV infection

Ideally, HIV infection should be diagnosed through routine testing before the patient becomes symptomatic. The Centers for Disease Control and Prevention (CDC) now recommends routine, voluntary HIV testing for all patients 13-64 years of age in all healthcare settings, regardless of perceived risk or health status. (The US Preventive Services Task Force recommends routine screening for all patients 15-65 years of age.)

HIV testing should also be performed in patients with symptoms suggestive of immunosuppression. These include unexplained weight loss, chronic diarrhea, fever, chills, sweats, dysphagia or odynophagia, oropharyngeal candidiasis (thrush), and more severe or frequent vaginal candidiasis.

Some skin conditions can be more severe or frequent in HIV-infected patients, including seborrheic dermatitis, psoriasis, dermatophyte infections, folliculitis, prurigo nodularis, anogenital or cutaneous herpes, anogenital warts or dysplasia, and herpes zoster (shingles).

Diagnoses that should prompt consideration of HIV testing include any infection associated with defective cellular immunity, lymphoma, Kaposi sarcoma, herpes zoster, tuberculosis, pneumonia, thrombocytopenia, or diseases that have similar risk factors, including sexually transmitted diseases, hepatitis B, and hepatitis C.

Physical findings that should prompt consideration of HIV testing include:

Testing for primary HIV infection is different from testing for chronic HIV infection, since standard serologic tests may be negative. Typical testing procedure involves either simultaneous HIV serology and HIV RNA (viral load) or the use of fourth-generation assays that test for both antibody and p24 antigen. HIV RNA will be positive approximately 5 days before the fourth generation test.

How did the patient develop HIV Infection? What was the primary source from which the infection spread?

HIV is acquired from person-to-person through contact with infected bodily fluids, usually semen, vaginal secretions, or blood. Modes of transmission include:

Sexual: most common, with unprotected receptive anal or vaginal intercourse being the activities associated with the greatest risk

Injection drug use: blood contact with shared syringes or needles

Perinatal transmission: infants born to mothers with unsuppressed viremia; transmission through breast-feeding also occurs

Transfusion/blood products: extremely rare form of transmission today due to testing of blood supply

HIV is not transmitted through kissing, sharing eating/drinking utensils, or contact with skin or saliva.

With all modes of transmission, the viral load (quantity of viral particles in the infected person's blood) is strongly associated with the risk of transmission.

The epidemiology of HIV infection varies, depending on geographical location. In the United States and other developed countries, men who have sex with men (MSM) and injection drug users are at higher risk than the general population. However, many infected individuals do not fall into traditional "high risk" categories, including heterosexual women who do not identify their male partner(s) as being at risk for HIV infection.

Traditional risk-based testing leads to under-diagnosis and has been replaced in the United States by routine voluntary testing regardless of risk. In many resource-limited settings, there is less of a gender difference in the prevalence of HIV infection, and heterosexual sex is the most common risk factor for infection.

Which individuals are of greater risk of developing HIV infection?

Risk factors for HIV infection are mostly epidemiologic and behavioral (see above) rather than biologic. However, some individuals are unlikely to be infected despite exposure This has been best characterized in individuals with the delta 32 deletion mutation resulting in a genetic absence of CCR5 co-receptors on the CD4+ cell surface. These co-receptors are required for entry of HIV into the cell.

Beware: there are other diseases that can mimic HIV infection:

Although there are other conditions that can cause cellular immunodeficiency with similar clinical manifestations, the sensitivity and specificity of the HIV serology make diagnostic confusion extremely unlikely. Patients who present with manifestations of cellular immunodeficiency should first be tested for HIV. Evaluation for other causes of immunodeficiency is indicated only if there is no laboratory evidence of HIV infection.

What laboratory studies should you order and what should you expect to find?

HIV serology: A positive fourth generation antigen/antibody test result (preferred) or positive enzyme immunoassay (EIA) with confirmatory Western blot establishes the diagnosis. (The exception is the rare false-positive result due to clerical or phlebotomist error. Repeat serology if viral load is very low or undetectable). Rapid HIV tests are highly sensitive, but positive results should be confirmed with standard serology or with a different rapid test. False-negative serologies can occur during the "window period": typically the first 2 weeks after infection. False-negatives are also more common with the OraSure In-Home rapid HIV test, when results are interpreted by the user. Some patients do not seroconvert for 3-4 weeks by conventional antibody tests; virtually all seroconvert within 6 months. The antigen/antibody tests have a shorter window period, decreasing the likelihood of false-negative results, including during acute or early infection.

HIV RNA (viral load): This is not typically used for diagnosis of chronic HIV infection, but should be ordered after diagnosis in all cases. Repeat and confirm HIV serology in patients with very low or undetectable viral loads. The use of either a combined antigen/antibody test or viral load testing is critical in cases of suspected primary HIV infection (acute retroviral syndrome), since standard serologies may be indeterminate or negative. It can also be useful when serology is indeterminate (positive EIA with presence of some bands on Western blot). Avoid using viral load in asymptomatic patients concerned about exposure, since serology is highly accurate and viral load can be false positive (low level result in HIV-uninfected patient) or false negative (undetectable viral load in infected elite controllers).

CD4+ cell count: The CD4+ cell count (CD4 count) neither confirms nor excludes the diagnosis of HIV infection but should always be ordered in patients diagnosed with HIV infection to determine immune status and to assess urgency of antiretroviral therapy and the need for opportunistic infection prophylaxis.

What imaging studies will be helpful in making or excluding the diagnosis of HIV infection?

Imaging studies are used to diagnose HIV-associated complications but are not helpful in diagnosing HIV infection itself. There are no imaging studies routinely recommended on the basis of a HIV diagnosis.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

HIV-infected patients should be managed, co-managed, or seen in consultation by an HIV expert, beginning as soon as possible after diagnosis.

There is currently no recognized medical subspecialty for HIV infection, and there are varying definitions of HIV expertise, which is generally defined by experience, patient load, and HIV-specific continuing medical education.

Some, but not all, HIV experts are infectious disease (ID) specialists; not all ID specialists are HIV experts.

Expert consultation is especially important in deciding when and how to initiate antiretroviral therapy (ART), in making changes to ART because of toxicity or failure, and in managing complications of HIV disease or ART.

If you decide the patient has HIV infection, what therapies should you initiate immediately?

ART is not an emergency, but it is urgent in the case of conditions that cannot be effectively treated without ART (e.g., HIV-associated dementia, HIV-associated nephropathy, PML, cryptosporidiosis, microsporidiosis, primary CNS lymphoma).

The benefit of ART for patients presenting with primary or recently acquired HIV infection remains uncertain, but some studies suggest benefit with very early therapy (preferably during symptomatic phase before seroconversion).

Current guidelines recommend ART for all HIV infected patients regardless of CD4 count, Need for immediate therapy depends mainly on CD4 count. OI prophylaxis can be started immediately, whereas ART can often be deferred briefly pending expert consultation.

CD4 greater than 500: ART should be initiated as soon as possible, but not urgent.

CD4 350-500: ART should be initiated as soon as possible, but not urgent.

CD4 less than 50: PCP and Toxoplasma prophylaxis should be initiated immediately. ART is urgent. Prophylaxis against Mycobacterium avium complex (MAC) is controversial. U.S. opportunistic infection guidelines recommend MAC prophylaxis if there is no evidence of disseminated disease, but International AIDS Society-USA (IAS-USA) guidelines do not recommend it if ART is to be started immediately.

Initiate ART immediately regardless of CD4 count:

HIV-associated nephropathy (HIVAN)

HBV co-infection

Pregnancy

History of AIDS-defining illness

Most acute opportunistic infections

Risk of transmission

The goal of ART is to reduce the viral load to levels below the limit of detection (generally <20 copies/mL).

ART regimens should be chosen based on resistance test results. This is true for the initial regimen, as well as subsequent regimens. Baseline genotypic resistance testing should be performed at the time of diagnosis, regardless whether ART will be initiated immediately. Baseline integrase resistance testing not currently recommended because of low risk of transmitted integrase mutations.

Resistance occurs when the virus is allowed to replicate in the face of selective drug pressure. This can occur when patients are treated with antiretroviral agents to which their virus is resistant or when drug levels are inadequate because of drug interactions, failure to follow food restrictions, or non-adherence with therapy.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection what anti-infective should I order?

The choice of initial ART regimen is rarely empiric. It should be chosen after a review of baseline genotypic resistance test results and then individualized based on specific patient characteristics.

The exception is the patient being treated during primary infection for whom resistance test results are not available. While waiting for resistance test results, a boosted protease inhibitor (PI)-based regimen or an integrase inhibitor-based regimen can be started, since transmitted resistance to these regimens is less likely. Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens should be avoided because of the possibility of transmitted NNRTI resistance.

For the Recommended and alternative antiretroviral regimens (DHHS July 14 2016) see Table I. For the Recommended Antiretroviral Regimens (IAS-USA Guidelines, July 2016) see Table II

Vaccinations (greater likelihood of immune response with higher CD4 count and undetectable viral load; vaccines may sometimes be deferred until CD4 greater than 200 on ART, or repeated after response to ART)

Streptococcus pneumoniae (pneumococcus)

Indications: All HIV+ patients

Pneumococcal vaccine-naïve persons. One dose of 13-valent pneumococcal vaccine (PCV13, Prevnar 13) followed by a dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23, Pneumovax) at least 8 weeks later and second dose of PPSV23 5 years later.

Previous vaccination with PPSV23: One dose of PCV13 ≥1 year after last PPSV23 dose. If second dose of PPSV23 required, should be given no sooner than 8 weeks after PCV13 and at least 5 years after the most recent dose of PPSV23.

Influenza A and B virus

Indications: All HIV+ patients

Dose: Inactivated influenza vaccine 0.5 mL IM annually

Hepatitis A virus (HAV)

Indications: Non-immune patients with chronic liver disease, injection drug users, men who have sex with men, travelers to endemic areas (or consider in all non-immune patients); consider deferral of vaccination until CD4 greater than 200

What should you tell the patient about his/her prognosis?

The prognosis of HIV infection is excellent in adherent patients without significant comorbid conditions.

Some modeling studies have estimated that life expectancy is the same as that of the general population in patients who achieve and maintain virologic suppression with good CD4 response to ART (e.g., CD4 > 500).

HIV infection is associated with elevated levels of immune activation and inflammation, which may have long-term consequences independent of CD4 count. These may include increased risk of coronary heart disease, malignancies, cognitive dysfunction, decreased bone density and fractures, and liver disease. Early initiation of ART lowers inflammation and immune activation and presumably decreases the risk of these complications, but possibly not to the same levels as in HIV-negative individuals.

How do you contract HIV infection and how frequent is this disease?

Epidemiology

United States

There are approximately 50,000 new cases of HIV infection each year. Approximately 1.1 million people were living with HIV infection by the end of 2010, 16% of whom do not know they are infected.

As of 2010, 63% of new cases were men who have sex with men, 25% were acquired through heterosexual contact, and 8% through injection drug use (IDU).

Global

It is estimated that there are 35 million people living with HIV worldwide, including 3.3 million children.

An estimated 2.3 million new infections occurred in 2012. Ninety-five percent of new infections occur in low- and middle-income countries, especially in sub-Saharan Africa.

There were 1.6 million AIDS deaths in 2012, and it is estimated that 36 million people have died since the beginning of the AIDS epidemic.

HIV infection is transmitted from person-to-person.

What pathogens are responsible for this disease?

HIV-1 is the most common cause of HIV/AIDS worldwide and in the United States. It is a lentivirus (member of retrovirus family) that infects human CD4 cells, macrophages, dendritic cells, and other human cells, establishing both latent and productive infection.

HIV-2 causes similar manifestations as HIV-1, but with slower progression and lower severity. It is seen primarily in West Africa or in people with West African exposures.

How do these pathogens cause HIV infection?

HIV infects CD4+ T-cells (helper T-cells), macrophages, dendritic cells, and other human cells. Patients with untreated HIV infection develop cellular immunodeficiency as a result of loss of CD4 cells, a result of direct viral killing of infected cells, increased rates of apoptosis in infected cells, and killing of infected CD4 cells by CD8 cytotoxic lymphocytes. Some long-term complications of HIV infection appear to be associated with elevated levels of inflammation and immune activation, which are reduced but not to normal levels by ART.

When should this disease be tested for?

Routine, voluntary HIV testing is recommended by the CDC for all patients 13-64 years of age and by the USPSTF for all patients 15-65 years of age, regardless of perceived risk or health status.

HIV testing should be performed in patients with symptoms suggestive of immunosuppression, including unexplained weight loss, chronic diarrhea, fever, chills, sweats, dysphagia or odynophagia, oropharyngeal candidiasis (thrush), and more severe or frequent vaginal candidiasis.

HIV testing should always be performed in patients with a history of tuberculosis, shingles, sexually transmitted infections, lymphoma, thrombocytopenia, hepatitis B, or hepatitis C, as well as in patients with AIDS-defining opportunistic infections or malignancies.

Anal Pap smears are recommended by HIVMA/IDSA HIV primary care guidelines in MSM or women with a history of anal sex; assess abnormal cytology with high resolution anoscopy

Toxoplasma IgG: If positive, give anti- Toxoplasma prophylaxis if CD4 is less than 100; if negative, counsel on prevention of infection (proper cooking of meat, avoidance of exposure to cat feces)

CMV IgG: Order in patients at low risk for CMV infection (assume latent infection in MSM and IDUs). If negative, counsel on prevention of infection (safe sex) and use CMV-negative blood products for transfusion

Testosterone level, free and total (AM) to diagnose hypogonadism in men with weight loss, depression, loss of libido, or erectile dysfunction

Cryptococcal antigen (serum) to diagnose cryptococcosis in patients with CD4 less than 100 who have fever, headache, or neurologic symptoms; sometimes recommended in all asymptomatic patients with CD4<100 to rule out subclinical cryptococcosis

"Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services". http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.

"Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medical Association of the Infectious Diseases Society of America". http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf.